Clinical Pearls for Practice: Cardiotoxicity of Chemotherapy

Guest post by:

Mark Pasetka    B.Sc., B.Sc.Pharm., Pharm.D.

Clinical Pharmacy Coordinator

Odette Cancer Centre – Sunnybrook Health Sciences Centre

CAPhO President-Elect

Author's Note: "This was a radiation therapy focused article – i.e., that was limited to 1000 words and therefore, short.  I focused on the 5-FU induced cardiotoxicity mostly and provided a very basic overview, not on anthracycline induced cardiotoxicity as is much more commonly reported."

Chemotherapy used for the treatment of cancer carry several significant side effects, but perhaps one of the most notable of these is cardiac toxicity.  There are several different types of cardiotoxicity (CTox) that may occur with a given treatment and may include heart failure (HF), myocardial ischaemia, thromboembolism, hypertension, left ventricular dysfunction (LVD), arrhythmias, and others.  The myocardium is known to have limited capacity to regenerate in comparison to some other tissues such as the gastrointestinal tract and subsequent damage from chemotherapy may be more pronounced or permanent in this case; however, some treatments are known to cause only transient and reversible toxicity.1

There are several treatments that have been shown to be associated with CTox (Table 1) and are typically assigned to one of two categories based on the potential for irreversible or reversible toxicity – Type I (irreversible) and Type II (reversible).2  Traditional chemotherapies are most commonly identified as Type I agents and the newer monoclonal antibodies and targeted treatments as Type II; however, there are instances where Type I agents cause reversible effects and Type II agents irreversible damage.2

The most commonly cited group of agents causing CTox are the anthracyclines, in particular doxorubicin.  Though the popular theory for the development of toxicity with anthracyclines is thought to be the creation of reactive oxygen species (ROS) leading to cardiomyocyte damage, new research suggests that pathways which include cardiomyocyte apoptosis or necrosis, impairment of cellular ability to produce adequate contraction, and modification of mitochondrial function may be involved.3,4

In the setting of concurrent radiation and chemotherapy treatment, agents commonly associated with cardiotoxic effects include the antimetabolites (5-fluorouracil and capecitabine) and the alkylating agents (mitomycin and cisplatin).  The latter of these, though uncommonly associated with direct cardiotoxic effects, has been noted to produce more myocardial ischemia when given in combination with 5-FU.1,5,6

The antimetabolites, 5-Fluorouracil (5-FU) and the pro-drug capecitabine, have been associated with cardiac ischemic effects that manifest as symptoms of angina.1,5,7,8 The incidence has been noted broadly in the literature with 5-FU (1-68%) and most often occurs within five days of initial administration; however, development of cardiac symptoms can occur in subsequent cycles of treatment as well as on rechallenge.1,5 Several other cardiac abnormalities have been reported in patients who have received 5-FU and include precordial chest pain, which may be anginal or non-cardiac in nature; additionally, there may or may not be changes in EKG parameters and myocardial enzymes may also appear normal.1  Although not definitively known, coronary artery thrombosis, coronary vasospasm, coronary arteritis, autoimmune responses, apoptosis of myocardial cells, and direct toxicity have been proposed as possible mechanisms.1,5,8

A recent systematic review by Polk et al., examined antimetabolite-induced cardiotoxicity, and identified the incidence of symptomatic cardiac effects in both 5-FU and capecitabine treated patients to be 0-20% and 3-35%, respectively.6 Palpitations, chest pain, dyspnoea, and hypotension were frequently reported, while heart failure was uncommon; more serious events such as myocardial infarction (MI), cardiogenic shock, and cardiac arrest occurred in up to two percent of patients.6 Risk factors for the development of cardiac symptoms varied between the included studies; for instance, four studies identified cardiovascular co-morbidities to be a risk factor whereas four others did not.6 Additionally, three of four studies identified continuous 5-FU infusion versus bolus dosing to be associated with a higher incidence of cardiotoxicity, suggesting that continued exposure may predict an increased incidence of cardiac effects.6

Mitomycin C (MMC), an alkylating agent commonly used in the treatment of anal cancer has been associated with an incidence of developing HF ranging from 3-16%.9 The risk for this effect is thought to occur when patients receive cumulative doses of MMC >30 mg/m2 as well as having received a prior or concurrent anthracycline.1,9,10 Interestingly it resembles the presentation of radiation-induced cardiac injury.1

The European Society of Medical Oncology (ESMO) created guidelines for the management of cardiotoxicity in cancer patients.  Recommendations for monitoring and management are summarized in table 3.2

Table 1. Potential cardiovascular effects of chemotherapies [Please note this is not a complete list].1,4-6,10-12

Note: Hypertension column not viewable due to size of table; medications: Regorafenib, Sorafenib, Sunitinib, Bevacizumab

Chemotherapy

Left Ventricular Dysfunction

Arrhythmias

Ischaemia

VTE

Hypertention

Angiogenesis

Inhibitors

 

Thalidomide

Thalidomide

Lenalidomide,

Thalidomide

 

Alkylating Agents

Cyclophosphamide,

Ifosphamide

Cyclophosphamide,

Ifosphamide,

Melphalan

Cisplatin

Cisplatin

 

Anthracyclines

Doxorubicin,

Liposomal Doxorubicin,

Epirubicin, Idarubicin

Doxorubicin

 

 

 

Anthraquinones

Mitoxantrone

 

 

 

 

Antimetabolites

Clofarabine

Capecitabine,

5-Fluorouracil,

Gemcitabine

5-Fluorouracil, Capecitabine

 

 

Anti-tumour

Antibiotic

Mitomycin C

 

 

 

 

Histone Deacetylase Inhibitors

 

Vorinostat

 

Vorinostat

 

Monoclonal

Antibodies

Bevacizumab,

Pertuzumab,

Trastuzumab

Alemtuzumab,

Cetuximab,

Rituximab,

Trastuzumab

Bevacizumab

Bevacizumab

Bevacizumab

Proteasome

Inhibitor

Bortezomib

 

 

 

 

Small Molecule Tyrosine Kinase Inhibitors

Dasatinib,

Imatinib,

Lapatinib,

Sunitinib

Dasatinib, Imatinib,

Lapatinib, Nilotinib,

Pazopanib, Sorafenib,

Sunitinib, Vandetinib

Erlotinib,

Sorafenib

Erlotinib

Regorafenib,

Sorafenib,

Sunitinib

Taxanes

Docetaxel,

Paclitaxel

Paclitaxel

Docetaxel, Paclitaxel

 

 

Other

 

Amsacrine,

Arsenic Trioxide

 

 

 

 

 

 

 

 

 

 

Table 2. Risk factors for the development of cardiotoxicity with chemo- and radiation therapy.2,5

Treatment Dependent

Patient Dependent

Chemotherapy

·       Type of chemotherapy

·       Dose of chemotherapy administered during each cycle

·       Cumulative dose

·       Schedule of administration

·       Route of administration

·       Combination of other cardiotoxic drugs or association with radiotherapy

Chemotherapy

·      Age

·      Presence of cardiovascular (CV) risk factors

·      Prior cardiovascular disease (CVD)

·      Prior mediastinal radiation therapy

Radiation

·       Dose >30-35 Gy

·       Dose per fraction >2 Gy

·       Large volume of irradiated heart

·       Longer time since exposure

·       Use of cytotoxic chemotherapy

·       Endocrine therapy or trastuzumab

Radiation

·      Younger age at exposure

·      Presence of CV risk factors

 

Table 3. Summarized ESMO recommendations for the monitoring and management of cardiotoxicity (CTox).2

Baseline Evaluation for Patients Receiving Chemotherapy

Cardiac Monitoring During Treatment with Chemotherapy

Treatment of LVD Induced by Chemotherapy

·       Baseline evaluation for CV risk factors and comorbidities and optimized management of these is essential

·       Patients who have received cumulative doses of anthracyclines or mitoxantrone should be considered to be at risk for CTox

·       Evaluation of LVEF, EKG status (including QT Time), Cardiac function via Echocardiography (or MUGA, or MRI), and Diastolic Function using US

·      Monitoring of cardiac function at baseline, 3, 6, and 9 months (during treatment) and 12 and 18 months following treatment initiation should occur for patients receiving anthracyclines and/or trastuzumab

·      Cardiac function evaluation at four and ten years should occur in patients who have achieved cumulative doses of doxorubicin (>240 mg/m2) and epirubicin (>360 mg/m2)

·      Depending on the reduction in LVEF whilst receiving anthracyclines or trastuzumab, require reassessment in three weeks; for more significant decreases in LVEF (i.e., to <40%), cessation of therapy, consideration of alternatives (if applicable), and treatment for LVD is indicated

·      In subclinical CTox induced by Type I agents, an ACE Inhibitor (enalapril) may prevent LVEF decrease and associated cardiac issues

·      Observation is indicated for patients who have developed asymptomatic CTox, with a LVEF ≥40% whilst on Type II agents (Trastuzumab) and have not received an anthracycline; persistence or worsening of status indicates treatment of LVD

·      Treatment of LVD is as per standard HF guidelines

 

References

1.     Perry MC et al. Chemotherapy Source Book. Nth Ed. 2013

2.     Curigliano C et al. Cardiovascular Toxicity Induced by Chemotherapy, Targeted Agents, and Radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012; 23 (Suppl 7): vii155-vii166

3.     Colombo A et al. Cardiac Toxicity of Anticancer Agents. Curr Cardiol Rep. 2013; 15 (362): 1-11

4.     Shaikh AY et al. Chemotherapy-Induced Cardiotoxicity. Curr Heart Fail Rep. 2012; 9: 117-127

5.     Bovelli D et al. Cardiotoxicity of Chemotherapeutic Agents and Radiotherapy-Related Heart Disease: ESMO Clinical Practice Guidelines. Ann Oncol. 2010; 21 (Suppl 5): v277-v282

6.     Polk A et al. Cardiotoxicity in Cancer Patients Treated with 5-Fluorouracil or Capecitabine: A Systemic Review of Incidence, Manifestations, and Predisposing Factors. Cancer Treat Rev. 2013; 39: 974-984

7.     Bonita R et al. Cardiovascular Toxicities of Cancer Chemotherapy. Semin Oncol. 2013; 40: 156-167

8.     Yeh ETH et al. Cardiovascular Complications of Cancer Therapy. J Am Coll Cardiol. 2009; 53 (24): 2231-2247

9.     British Columbia Cancer Agency. Selected monographs for Mitomycin C

10.  Cancer Care Ontario. Selected monographs for Bevacizumab, Regorafenib

11.  Albini A et al. Cardiotoxicity of Anticancer Drugs: The Need for Cardio-Oncology and Cardio-Oncological Prevention. J Nat Cancer Inst. 2010; 102(1): 14-25

12.  Guglin, M et al. Introducing a New Entity: Chemotherapy-Induced Arrhythmia. Eurospace: Eur Soc Cardiol. 2009; 11: 1579-1586

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